Alcohol abuse is the single most common known and preventable cause of birth defects, and a major contributor to both chronic liver disease and neurodegeneration in the United States. Our research has linked several chronic alcohol exposure-mediated abnormalities in brain and liver function to impairments in insulin and insulin-like growth factor signaling, particularly with regard to cell survival and energy metabolism. However, in order to capitalize on these recent gains, it will be necessary to extend the analyses to human disease states using state-of-the-art methodology. The major goals of this proposal are to: 1) investigate mechanisms of alcohol-mediated neurodegeneration in adult human brains using molecular and biochemical approaches;2) provide a strong, highly supportive environment to train and mentor junior investigators, particularly physician-scientists, to investigate human disease mechanisms by utilizing current technology to analyze human tissue samples;and 3) educate junior investigators about the importance of experimental models for testing hypotheses and validating results from human studies. Emphasis will be placed on including women and minority trainees. Suzanne M. De la Monte is a Pathologist and Neuropathologist by training and clinical activities at the Rhode Island Hospital, and Professor of Pathology and Clinical Neuroscience at Brown University. Dr. De la Monte has a long track record of training young investigators in human disease, biomedical, and translational research. Her laboratory, which currently is supported by NIH funding from NIAAA, hosts several trainees including undergraduates, medical students, graduate students, postdoctoral fellows, and junior physician-scientists, most of whom are women or members of under-represented minority groups. This Mid-career investigator award will provide better opportunity for Dr. De la Monte to exercise leadership and high quality mentorship and training of promising young scientists. The information included in this application demonstrates a productive career in human and translational research, and demonstrates Dr. De la Monte's commitment to continuing this type of work while mentoring scientists for the future.